Organ-VIP · Genetically modified organoids for genetic variant interpretation in colorectal cancer
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-09-01 → 2022-08-31
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Genetically modified organoids for genetic variant interpretation in colorectal cancer
Colorectal cancer (CRC) is the fourth leading cause of cancer death, being the second most common cancer in women and the third in men. Environmental and genetic factors play a key role in the development of this disease, and 10-20% of the cases correspond to familial or hereditary forms. Although several genes have been causally linked to a predisposition to CRC and/or polyposis, there is still a high proportion of patients with familial and/or early-onset CRC that do not carry pathogenic variants in any of the known hereditary cancer genes. In the last decades, Next Generation Sequencing (NGS) technologies have boosted the discovery of candidate CRC predisposition genes, and the identification of variants of unknown significance (VUS) in known hereditary cancer genes. However, until the causal link of those candidate genes with cancer is confirmed, and the pathogenic or benign nature of the variants is dilucidated, they lack clinical value. The identification of a pathogenic variant in a cancer predisposition gene significantly improves the clinical management of the individual carrier, through the application of individualised surveillance protocols based on the corresponding cancer risks, and in some cases, of personalized oncologic treatments based on targeted therapies. Variant classification largely relies on clinical data (cosegregation data, tumour molecular features); however, these are often unavailable, leaving the functional experimental evidence to be decisive for variant classification. The project to be developed by the MSCA-IF grantee is aimed to develop a platform based on genetically modified intestinal organoids for the functional characterization of variants and genes affecting Wnt signalling, BMP/TGF-beta pathway, or DNA repair mechanisms. The specific objectives are: (a) to implement and optimize the intestinal organoid culture, gene editing and gene-specific functional tests in the host lab to study VUS potentially involved in the development of hereditary CRC (hCRC); (b) to assess VUSs in hereditary CRC and polyposis genes affecting the different pathways/mechanisms mentioned above; and (c) to calibrate the obtained functional results for implementation of variant classification guidelines. On the other hand, this fellowship is also focused on the training and development of skills for the development of the Fellow’s professional career.
Data: CORDIS, © European Union
Project objective
Implementation of next generation sequencing to genetic diagnosis and precision medicine has revolutionized the fields of hereditary cancer and oncology, increasing exponencially the identification of genetic variants of uncertain significance. Their classification is one of the most relevant and urgent challenges we face, since decision-making in the clinics depends on it. Evidence obtained from empirical functional studies is essential to reach a definitive classification; however, clinical relevance of such studies is currently low due to lack of standardized tests, use of inadequate models, and tediousness and cost- and time-inefficiency of available assays. Organ-VIP aims at surpassing the barriers we face when using and implementing functional assays for the interpretation of genetic variants in colorectal cancer (CRC) genes. State-of-the-art methodological and conceptual developments will facilitate the development of a screening platform to interpret the pathogenicity of variants in any CRC gene. To do so, we aim to: i) Use a model that faithfully represents the target tissue and genetic context (CRISPR/Cas9-edited human normal colon organoids); ii) Optimize end-point assay(s) to maximize performance, implementation, robustness and agreement with clinical evidence; iii) Assess genetic variants in hereditary CRC and polyposis genes; and iv) Calibrate the results for implementation in variant classifiers. Organ-VIP integrates clinical aspects, molecular and cell biology, next generation sequencing, and advanced bioinformatics analysis. The platform will not only be useful for variant interpretation in germline and somatic testing, but also for functional evaluation of new candidate CRC genes. In the longer term, Organ-VIP will become high-throughput by the implementation of saturation genome editing, high-throughput organoid culture, automation of sampling, and implementation of artificial intelligence.
Original text from CORDIS.
Participants
- FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE · L'Hospitalet De LlobregatCoordinatorSpain
Links
Data: CORDIS, © European Union